Understanding upstream open reading frame (uORF) functions in the context of dendritic cells biology by computational and experimental approaches
The development of high-throughput technologies revealed the existence of non-canonical short open reading frames (sORFs) on most eukaryotic RNAs. Upstream ORFs (uORFs) have been defined as sORFs preceding the main coding sequence (CDS). They are ubiquitous elements conserved across species that may be key players of the translational regulation. To date, uORFs have been essentially reported to be gene expression cis-regulatory elements. By reducing the efficiency of translation initiation of the main CDS, uORFs participate to the translational regulatory mechanisms, notably during cellular stress. In mammals, dendritic cells (DCs) play a pivotal role in the immune system by orchestrating both the innate and adaptive responses. While upon infection, the sensing of the pathogen by the DCs may be responsible of a global translational arrest, the concomitant up-regulation of the expression of some proteins has been highlighted. The uORFs may be responsible of the preferential expression of some particular CDSs. Moreover, the discovery of uORF-encoded peptides (sPEPs) led to the assumption that they may also play functional roles in trans. Indeed, DCs process peptides to be loaded on major histocompatibility complex (MHC) molecules. These peptides could be encoded by uORFs.
My PhD project aims to decipher the functions of the uORFs in the dendritic cells activation by combining experimental and computational approaches. In this project we are thus (i) building a resource database of sORFs identified in the human and mouse genomes, to explore (ii) the cis-regulatory potential and (iii) the trans functions of the uORFs in these species.
- (i) Publicly available data has been gathered to characterize the sORFs. The curation of data from computational predictions, Ribo-seq and proteomic experiments and the merging of the redundant information into unique entries represent the added value of this database. This notably enables analysis at gene level.
- (ii) The database will be exploited to investigate the possible regulatory role of the uORFs in the translation of stress-induced transcription factors, and to propose a model of translation regulation by the uORFs that will then be assessed by experimental validations.
- (iii) A pipeline recently developed by our team allows inferring peptide-protein interactions. It will be used in order to build the first sPEPs-protein interactome that will be explored to scrutinize sORFs trans functions.
- Christine Brun (TAGC)
- Philippe Pierre (CIML)
- Pierre Milpied (CIML)
- Benoit Ballester (TAGC)
- François Payre (CBI)
- Lionel Spinelli (TAGC, CIML)
- Andreas Zanzoni (TAGC)
- Choteau SA, Wagner A, Pierre P, Spinelli L, Brun C (2021). MetamORF: A repository of unique short Open Reading Frames identified by both experimental and computational approaches for gene-level and meta-analysis (2021). Database, Under review.
- Mendes A, Gigan JP, Rodriguez Rodrigues C, Choteau SA, Sanseau D, Barros D, Almeida C, Camosseto V, Chasson L, Paton AW, Paton JC, Argüello RJ, Lennon-Duménil A, Gatti E, Pierre P. Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4 (2020). Life Science Alliance. 21;4(2):e202000865. doi: 10.26508/lsa.202000865.
- Cold Spring Harbor Laboratory Network Biology Meeting 2021 - Poster
- Journées Ouvertes de Bioinformatique et Mathématique (JOBIM) 2020 - Poster
- CENTURI scientific days (3 events) - Poster
- TAGC internal seminars
- CIML internal seminars
- Various short talks and presentations (CIML and CENTURI PhD welcome days, PhD workshops etc.)
- Co-representative of the PhD and master students at the TAGC lab council (2018-2019)
- Representative of the PhD students at the CENTURI education and steering committees (2018-2021)
- Member of the CENTURI team dedicated to the organization of tutored seminars (2018-2020)
- Member of the organization committee of the CENTURI PhD student & PostDoc scientific day (2020)
- Member of the organization committee of the CIML annual PhD workshop (2020)
- MetamORF website: https://metamorf.hb.univ-amu.fr
- CENTURI PhD fellowship (2018 - 2021)
Please, feel free to contact me if you are willing to talk about my PhD project and the projects I am or have been involved in.